Understanding Atypical Haemolytic Uraemic Syndrome (aHUS) Differential Diagnosis of Thrombotic Microangiopathies (TMAs)

An Algorithm to Diagnose Thrombotic Microangiopathy (TMA) A TMA is defined by: Thrombocytopenia1,3 Platelet count <150 x 109 /L or >25% decrease from baseline1 Microangiopathic hemolysis1,3 Schistocytes1,3 and/or Elevated LDH2 and/or Decreased haptoglobin1 and/or Decreased haemoglobin3 AND Plus 1 or more of the following: Neurological symptoms4-8 Confusion4-6 and/or Seizures4,6 and/or Other cerebral abnormalities7,8 Renal impairment2,9,10-12 Elevated creatinine2 and/or Decreased eGFR12 and/or Elevated blood pressure9 and/or Abnormal urinalysis10 Gastrointestinal symptoms2,6,13,14 Diarrhoea ± blood5 and/or Nausea/vomiting6 and/or Abdominal pain6 and/or Gastroenteritis2,12 1. Caprioli J. Blood. 2006;108:1267–1279. 2. Data on file. Alexion Pharmaceuticals, Inc.; 2014. 3. Sellier-Leclerc A-L. JASN. 2007;18:2392–2400. 4. Noris M. New England Journal of Medicine. 2009;361:1676–1687. 5. Neuhaus TJ. Arch Dis Child. 1997;76:518–521. 6. Ohanian M. Clinical Pharmacology: Advances and Applications. 2011;5. 7. Dragon-Durey M-A. J Am Soc Nephrol. 2010;21:2180–2187. 8. Noris M. JASN. 2005;16:1177–1183. 9. Davin J-C. American Journal of Kidney Diseases. 2010;55:708–711. 10. Sallée M. Nephrol Dial Transplant. 2010;25:2028–2032. 11. Al-Akash SI. Pediatr Nephrol. 2011;26:613–619. 12. Benz K. Curr Opin Nephrol Hypertens. 2010;19:242–247. 13. Boyer O. American Journal of Kidney Diseases. 2010;55:923–927. 14. Noris M. Clin J Am Soc Nephrol. 2010;5:1844–1859. 15. Zuber J. Nat Rev Nephrol. 2011;7:23–35. 16. Tsai H-M. Int J Hematol. 2010;91:1–19. 17. Bianchi V. Blood. 2002;100:710–713. 18. Barbot J. British Journal of Haematology. 2001;113:649–651. 19. Sadler JE. Blood. 2008;112:11–18. 20. Bitzan M. Semin Thromb Hemost. 2010;36:594–610. 21. Zuber J. Nat Rev Nephrol. 2012;8:643–657. 22. Coppo P. PLoS One. 2010;5. Definitions: eGFR = estimated glomerular filtration rate; STEC = Shiga toxin–producing Escherichia coli. References: 1. Caprioli J. Blood. 2006;108:1267–1279. 2. Sellier-Leclerc A-L. JASN. 2007;18:2392–2400. 3. Noris M. New England Journal of Medicine. 2009;361:1676–1687. 4 .Neuhaus TJ. Arch Dis Child. 1997;76:518–521. 5. Ohanian M. Clinical Pharmacology: Advances and Applications. 2011;5. 6. Dragon-Durey M-A. J Am Soc Nephrol. 2010;21:2180–2187. 7. Noris M. JASN. 2005;16:1177–1183. 8. Davin J-C. American Journal of Kidney Diseases. 010;55:708–711. 9. Sallée M. Nephrol Dial Transplant. 2010;25:2028–2032. 10. Al-Akash SI. Pediatr Nephrol. 2011;26:613–619. 11. Benz K. Curr Opin Nephrol Hypertens. 2010;19:242–247. 12. Boyer O. American Journal of Kidney Diseases. 2010;55:923–927. 13. Noris M. Clin J Am Soc Nephrol. 2010;5:1844–1859. 14. Zuber J. Nat Rev Nephrol. 2011;7:23–35.

Normal ADAMTS13 Activity Understanding How the Pathophysiology of TTP vs. aHUS Underscores the Need for Differential Treatment TTP Insufficient ADAMTS13 activity (≤5%) leaves von Willebrand factor intact1-4 Treatment goal: Suppress inhibitor autoantibody; replace ADAMTS13 PE/PI replenishes ADAMTS13 and decreases autoantibodies5,6 aHUS Genetic defects lead to chronic uncontrolled activation of the complement system7-12 Treatment goal: Inhibit ongoing complement activation PE/PI fails to inhibit complement activity that drives pathophysiology in aHUS5,10 Classical Pathway Alternative Pathway Lectin Pathway Normal ADAMTS13 Activity ADAMTS13 deficiency vWF cleaved vWF uncleaved Apheresis procedures themselves may lead to complement activity via granulocyte aggregation13 Definitions: PE/PI = plasma exchange/plasma infusion. References: 1. Tsai H-M. Int J Hematol. 2010;91:1–19. 2. Sadler JE. Blood. 2008; 112:11–18. 3. Moake JL. N Engl J Med. 2002;347:589–600. 4. Tsai H-M. Am J Med. 2013;126:200–209. 5. Laurence J. Clin Adv Hematol Oncol. 2012;10(10 suppl 17):1–12. 6. Barbot J et al. Br J Haematol. 2001;113:649–651. 7. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859. 8. Noris M et al. N Engl J Med. 2009;361:1676–1687. 9. Holers VM. Immunol Rev. 2008;223: 300–316. 10. Loirat C et al. Orphanet J Rare Dis. 2011;6:60. 11. Fang CJ et al. Br J Haematol. 2008;143:336–348. 13. Boogaerts MA et al. Transfusion. 1986;26:82–87.

Different TMAs Have Different Etiologies and Require Different Management Approaches1-11 Note: The diagram is for illustrative purposes only; disease areas are not drawn to proportional scale and are not meant to reflect relative incidence. References: 1. George JN. Kidney Int. 2009;75:S8–S10. 2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;19:372-378. 3. Ornstein BW. Curr Opin Rheumatol. 2012;24:522–529. 4. Zhang B. Hypertens Res. 2008;31:479–483. 5. Fakhouri F. J Am Soc Nephrol. 2010;21:859–867. 6. Noris M et al. Nat Rev Nephrol. 2012;8:622–633. 7. Campistol JM et al. Nefrologia. 2013;33:27–45. 8. Totina A et al. Clin Pediatr (Phila). 2011;52:183–186. 9. Kavanagh D et al. Br Med Bull. 2006;77-78:5-22. 10. Bitzan M. Semin Thromb Hemost. 2010;36:594–610. 11. Tsai H-M. Int J Hematol. 2010;91:1–19.

Different TMAs Have Different Etiologies and Require Different Management Approaches1-11 TMA Associated with a Complement Amplifying Condition: Infection induced1,2 Autoimmune disorders (ie: SLE)3 Malignant hypertension4 Pregnancy associated5 Drug mediated1 TMA Note: The diagram is for illustrative purposes only; disease areas are not drawn to proportional scale and are not meant to reflect relative incidence. References: 1. George JN. Kidney Int. 2009;75:S8–S10. 2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;19:372-378. 3. Ornstein BW. Curr Opin Rheumatol. 2012;24:522–529. 4. Zhang B. Hypertens Res. 2008;31:479–483. 5. Fakhouri F. J Am Soc Nephrol. 2010;21:859–867. 6. Noris M et al. Nat Rev Nephrol. 2012;8:622–633. 7. Campistol JM et al. Nefrologia. 2013;33:27–45. 8. Totina A et al. Clin Pediatr (Phila). 2011;52:183–186. 9. Kavanagh D et al. Br Med Bull. 2006;77-78:5-22. 10. Bitzan M. Semin Thromb Hemost. 2010;36:594–610. 11. Tsai H-M. Int J Hematol. 2010;91:1–19.

Different TMAs Have Different Etiologies and Require Different Management Approaches1-11 aHUS Unmasked by a Complement Amplifying Condition6-9 TMA TMA Associated with a Complement Amplifying Condition: Infection induced1,2 Autoimmune disorders (ie: SLE)3 Malignant hypertension4 Pregnancy associated5 Drug mediated1 aHUS without a Complement Amplifying Condition6-9 Note: The diagram is for illustrative purposes only; disease areas are not drawn to proportional scale and are not meant to reflect relative incidence. References: 1. George JN. Kidney Int. 2009;75:S8–S10. 2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;19:372-378. 3. Ornstein BW. Curr Opin Rheumatol. 2012;24:522–529. 4. Zhang B. Hypertens Res. 2008;31:479–483. 5. Fakhouri F. J Am Soc Nephrol. 2010;21:859–867. 6. Noris M et al. Nat Rev Nephrol. 2012;8:622–633. 7. Campistol JM et al. Nefrologia. 2013;33:27–45. 8. Totina A et al. Clin Pediatr (Phila). 2011;52:183–186. 9. Kavanagh D et al. Br Med Bull. 2006;77-78:5-22. 10. Bitzan M. Semin Thromb Hemost. 2010;36:594–610. 11. Tsai H-M. Int J Hematol. 2010;91:1–19.

Different TMAs Have Different Etiologies and Require Different Management Approaches1-11 aHUS Unmasked by a Complement Amplifying Condition6-9 TMA TMA Associated with a Complement Amplifying Condition: Infection induced1,2 Autoimmune disorders (ie: SLE)3 Malignant hypertension4 Pregnancy associated5 Drug mediated1 aHUS without a Complement Amplifying Condition6-9 TTP (severe ADAMTS13 deficiency)11 Note: The diagram is for illustrative purposes only; disease areas are not drawn to proportional scale and are not meant to reflect relative incidence. References: 1. George JN. Kidney Int. 2009;75:S8–S10. 2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;19:372-378. 3. Ornstein BW. Curr Opin Rheumatol. 2012;24:522–529. 4. Zhang B. Hypertens Res. 2008;31:479–483. 5. Fakhouri F. J Am Soc Nephrol. 2010;21:859–867. 6. Noris M et al. Nat Rev Nephrol. 2012;8:622–633. 7. Campistol JM et al. Nefrologia. 2013;33:27–45. 8. Totina A et al. Clin Pediatr (Phila). 2011;52:183–186. 9. Kavanagh D et al. Br Med Bull. 2006;77-78:5-22. 10. Bitzan M. Semin Thromb Hemost. 2010;36:594–610. 11. Tsai H-M. Int J Hematol. 2010;91:1–19.

Different TMAs Have Different Etiologies and Require Different Management Approaches1-11 TMA Associated with a Complement Amplifying Condition: Infection induced1,2 Autoimmune disorders (ie: SLE)3 Malignant hypertension4 Pregnancy associated5 Drug mediated1 aHUS Unmasked by a Complement Amplifying Condition6-9 aHUS without a Complement Amplifying Condition6-9 STEC-HUS10 TTP (severe ADAMTS13 deficiency)11 Note: The diagram is for illustrative purposes only; disease areas are not drawn to proportional scale and are not meant to reflect relative incidence. References: 1. George JN. Kidney Int. 2009;75:S8–S10. 2. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;19:372-378. 3. Ornstein BW. Curr Opin Rheumatol. 2012;24:522–529. 4. Zhang B. Hypertens Res. 2008;31:479–483. 5. Fakhouri F. J Am Soc Nephrol. 2010;21:859–867. 6. Noris M et al. Nat Rev Nephrol. 2012;8:622–633. 7. Campistol JM et al. Nefrologia. 2013;33:27–45. 8. Totina A et al. Clin Pediatr (Phila). 2011;52:183–186. 9. Kavanagh D et al. Br Med Bull. 2006;77-78:5-22. 10. Bitzan M. Semin Thromb Hemost. 2010;36:594–610. 11. Tsai H-M. Int J Hematol. 2010;91:1–19.

The Pathophysiology of aHUS Is Driven by Uncontrolled Activation of Complement

Subendothelial matrix Endothelial-cell damage In aHUS, Complement Dysregulation Leads to Chronic, Uncontrolled Complement Activation1-11 Lectin pathway Classical pathway Alternative pathway C3 Amplification Proximal Gain of function mutations: C3, CFB C3b Loss of function mutations: CFH, CFI, MCP, THBD, anti-CFH antibodies + – C3-Convertase C5-Convertase Platelets Platelet activation Anaphylaxis Inflammation Thrombosis . PMP C5a C5 Terminal Coagulation C5b-9 deposition on endothelial cell Proteinases Oxygen radicals C5b C5b-9 Thrombus formation Endothelial cell Endothelial injury Subendothelial matrix Endothelial-cell damage and retraction References: 1. Figueroa JE et al. Clin Microbiol Rev. 1991;4:359–395. 2. Walport MJ. N Engl J Med. 2001;344:1058–1066. 3. Rother RP et al. Nat Biotechnol. 2007;25:1256–1264. 4. Parker C et al. Blood. 2005;106:3699–3709. 5. Caprioli J et al. Blood. 2006;108:1267–1279. 6. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859. 7. George JN. Blood. 2010;116:4060–4069. 8. Loirat C et al. Pediatr Nephrol. 2008;23:1957–1972. 9. Ståhl AL et al. Blood. 2008;111:5307–5315. 10. Hosler GA et al.  Arch Pathol Lab Med. 2003;127;834–839. 11. Ariceta G et al. Pediatr Nephrol. 2009;24:687–696.

aHUS Is a Chronic Disease with Life-Threatening Consequences: Mortality is Not Altered by PEx1,2 Patients progressing to ESRD, permanent renal damage, or death 100 80 79%1 60 Patients, % 40 33%-40%1,2 20 Across two studies, among a total 378 patients with available data, 289 patients (76%) received PE/PI. In Caprioli, et al 2006, (N=156) 109 patients out of 128 patients with available data (85%) received PE/PI during the first episode of aHUS.2 In Noris, et al 2010 (N = 273) 180 patients out of 250 patients with available data (72%) received PE/PI treatment for aHUS. Definitions: ESRD = end stage renal disease.1 References: Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-1859. 2. Caprioli et al. Blood. 2006;108:1267-1272. First clinical manifestation (Death or ESRD) 3 years after diagnosis References: 1. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859. 2. Caprioli et al. Blood. 2006;108:1267–1272.

aHUS Is a Systemic TMA that Affects Multiple Organs and Tissues*1-17 Renal: More than 50% of patients progress to ESRD1 Elevated creatinine2,3 Proteinuria4 Edema,3 malignant hypertension5 Decreased eGFR6 CNS: Up to 48% of patients experience neurological symptoms4 Confusion7 Stroke7 Encephalopathy5 Seizure4 Blood: Thrombocytopenia1 Decreased haptoglobin1 Elevated lactate dehydrogenase (LDH)1 Decreased haemoglobin1 Schistocytes1 Visual: Ocular occlusion8 Cardiovascular: Up to 43% of patients experience cardiovascular symptoms4 Myocardial infarction9,10 Hypertension11 Diffuse vasculopathy6 Peripheral gangrene10 Gastrointestinal: 37% of patients experience GI symptoms13 Diarrhoea14 Colitis7 Nausea/Vomiting15 Pancreatitis15 Abdominal pain7 Gastroenteritis4 Liver necrosis4 Pulmonary: 47% of patients experience pulmonary symptoms15 Dyspnoea9 Pulmonary haemorrhage16 Pulmonary edema9 Footnote: *The organ-specific symptoms associated with aHUS are reported from published literature and are not limited to only those listed above. Definition: eGFR = estimated glomerular filtration rate. References: 1. Caprioli et al. Blood. 2006;108:1267-1272. 2. Ariceta G et al; for the European Paediatric Study Group for HUS. Pediatr Nephrol. 2009;24:687–696. 3. Ståhl A-L et al. Blood. 2008;111:5307–5315. 4. Neuhaus TJ et al. Arch Dis Child. 1997;76:518–521. 5. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859. 6. Loirat C et al. Pediatr Nephrol. 2008;23:1957–1972. 7. Ohanian M et al. Clin Pharmacol. 2011; 3:5–12. 8. Larakeb A et al. Pediatr Nephrol. 2007;22:1967–1970. 9. Sallée M et al. Nephrol Dial Transplant. 2010;25:2028–2032. 10. Noris M et al. Nat Rev Nephrol. 2014;10:174–180. 11. Kavanagh D et al. Med Bull. 2006;77-78:5–22. 12. Malina M et al. Pediatr Nephrol. 2011;26:1678. 13. Langman C. Haematologica. 2012;97(s1):195–196. 14. Dragon-Durey M-A et al. J Am Soc Nephrol. 2010;21:2180–2187.15.Muus P. Presented at: 18th Congress of the European Hematology Association. June 13-16, 2013; Stockholm, Sweden. Abstract B1774. 16. Sellier-Leclerc A-L et al; French Society of Pediatric Nephrology. J Am Soc Nephrol. 2007;18:2392–2400.

Understanding aHUS in the Differential Diagnosis of TMA

Defining aHUS1,2 1. Signs and symptoms of a TMA1,2 Decreased platelet count1 Evidence of microangiopathic haemolysis1 Signs and symptoms of organ impairment/damage (eg, serum creatinine > ULN)2,3 2. Differentiation from other TMAs1,2 ADAMTS13 activity >5% → excludes severe ADAMTS13 deficiency (congenital or acquired TTP) Absence of positive STEC test → excludes STEC as sole cause of TMA 3. No requirement for identified complement gene mutation1,2 Genetic mutation cannot be identified in 30% to 50% of patients with aHUS Definition: STEC = Shiga toxin–producing Escherichia coli. References: 1. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859. 2. Tsai H-M. Int J Hematol. 2010;91:1–19.

While Not Required for Diagnosis, Identification of Specific Genetic Mutations May Have Prognostic Value1-5 aHUS is diagnosed clinically and diagnosis does not require identification of a mutation1,2,5 A genetic mutation cannot be identified in 30% to 50% of patients with aHUS1-3 Regardless of whether or not a mutation is identified, patients with aHUS have similarly devastating outcomes3 Genetic testing may be important in genetic counseling of family members and may impact long-term patient outcomes3,4 References: 1. Kavanagh D. Br Med Bull. 2006;77-78:5–22. 2. Kavanagh D. Hematology. 2011;2011:15–20. 3. Noris M. Clin J Am Soc Nephrol. 2010;5: 1844–1859. 4. Bresin E. J Am Soc Nephrol. 2013;24:475–486. 5. Laurence J. Clin Adv Hematol Oncol. 2012;10:1–12..

Measuring Complement Protein Levels Is Not Required for a Diagnosis of aHUS1-3 Assays for the measurement of complement protein and soluble complement regulatory factors have not been validated for clinical decision making in the treatment of patients with aHUS1 Complement dysregulation is implicated in patients whose C3 levels are low, but normal C3 levels do not exclude a diagnosis of aHUS2 Most patients with aHUS have normal levels of complement proteins3 Serum levels of C3 are normal in approximately 80% of patients with aHUS3 Complement Factor H (CFH) levels are normal in approximately 50% of patients with aHUS who have a mutation in CFH3 References: 1. Cugno M. J Thromb Haemost. 2014;12:1440–1448. 2. Laurence J. Clin Adv Hematol Oncol. 2012;10:1-12. 3. Geerdink LM. Pediatr Nephrol. 2012;27:1283–1291.

The Difficulty of Diagnosing aHUS Clinical presentation can be similar to other systemic TMAs1-4 aHUS is a rare disease, leading to lack of clinical suspicion5 Associated complement amplifying conditions may confound the diagnosis of aHUS6 References: 1. George JN. Blood. 2010;116:4060–4069. 2. Noris M et al. N Engl J Med. 2009;361:1676–1687. 3. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;19:372–378. 4. Bianchi V et al. Blood. 2002;100:710-713. 5. Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol. 2009;24:687–696. 6. Kavanagh D et al. Br Med Bull. 2006;77-78:5–22.

Differential Diagnosis for TMAs: aHUS, TTP, and STEC-HUS Thrombocytopenia1,3 Platelet count <150 x 109/L or >25% decrease from baseline1 Microangiopathic hemolysis1,3 Schistocytes1,3 and/or Elevated LDH1 and/or Decreased haptoglobin3 and/or Decreased haemoglobin3 AND Plus 1 or more of the following: Neurological symptoms4-8 Confusion4-6 and/or Seizures4,6 and/or Other cerebral abnormalities7,8 Renal impairment2,9,10-12 Elevated creatinine2 and/or Decreased eGFR12 and/or Elevated blood pressure9 and/or Abnormal urinalysis10 Gastrointestinal symptoms2,6,13,14 Diarrhea ± blood5 and/or Nausea/vomiting6 and/or Abdominal pain6 and/or Gastroenteritis2,12 Evaluate ADAMTS13 activity and Shiga-toxin/EHEC test14 While ADAMTS13 results are awaited, a platelet count >30 x 109/L or serum creatinine >1.7-2.3 mg/dL almost eliminates a diagnosis of severe ADAMTS13 deficiency (TTP)14 References: 1. Caprioli J. Blood. 2006;108:1267–1279. 2. Data on file. Alexion Pharmaceuticals, Inc.; 2014. 3. Sellier-Leclerc A-L. JASN. 2007;18:2392–2400. 4. Noris M. New England Journal of Medicine. 2009;361:1676–1687. 5. Neuhaus TJ. Arch Dis Child. 1997;76:518–521. 6. Ohanian M. Clinical Pharmacology: Advances and Applications. 2011;5. 7. Dragon-Durey M-A. J Am Soc Nephrol. 2010;21:2180–2187. 8. Noris M. JASN. 2005;16:1177–1183. 9. Davin J-C. American Journal of Kidney Diseases. 2010;55:708–711. 10. Sallée M. Nephrol Dial Transplant. 2010;25:2028–2032. 11. Al-Akash SI. Pediatr Nephrol. 2011;26:613–619. 12. Benz K. Curr Opin Nephrol Hypertens. 2010;19:242–247. 13. Boyer O. American Journal of Kidney Diseases. 2010;55:923–927. 14. Noris M. Clin J Am Soc Nephrol. 2010;5:1844–1859. 15. Zuber J. Nat Rev Nephrol. 2011;7:23–35. 16. Tsai H-M. Int J Hematol. 2010;91:1–19. 17. Bianchi V. Blood. 2002;100:710–713. 18. Barbot J. British Journal of Haematology. 2001;113:649–651. 19. Sadler JE. Blood. 2008;112:11–18. 20. Bitzan M. Semin Thromb Hemost. 2010;36:594–610. 21. Zuber J. Nat Rev Nephrol. 2012;8:643–657. 22. Coppo P. PLoS One. 2010;5. ≤5% ADAMTS13 activity14 >5% ADAMTS13 activity14 Shiga toxin/EHEC positive14 TTP aHUS STEC-HUS This information is intended as educational information for health care providers. It does not replace a health care professional’s judgment or clinical diagnosis. References: 1. Caprioli J. Blood. 2006;108:1267–1279. 2. Sellier-Leclerc A-L. JASN. 2007;18:2392–2400. 3. Noris M. New England Journal of Medicine. 2009;361:1676–1687. 4 .Neuhaus TJ. Arch Dis Child. 1997;76:518–521. 5. Ohanian M. Clinical Pharmacology: Advances and Applications. 2011;5. 6. Dragon-Durey M-A. J Am Soc Nephrol. 2010;21:2180–2187. 7. Noris M. JASN. 2005;16:1177–1183. 8. Davin J-C. American Journal of Kidney Diseases. 010;55:708–711. 9. Sallée M. Nephrol Dial Transplant. 2010;25:2028–2032. 10. Al-Akash SI. Pediatr Nephrol. 2011;26:613–619. 11. Benz K. Curr Opin Nephrol Hypertens. 2010;19:242–247. 12. Boyer O. American Journal of Kidney Diseases. 2010;55:923–927. 13. Noris M. Clin J Am Soc Nephrol. 2010;5:1844–1859. 14. Zuber J. Nat Rev Nephrol. 2011;7:23–35

Patient / Family Medical History Patient and Family Medical History May Provide Evidence of Previously Undiagnosed aHUS1 Patient / Family Medical History History of previous TMA Unexplained renal failure Malignant/severe hypertension Myocardial infarction Preeclampsia with renal involvement that persisted after pregnancy References: 1. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859

Diagnosing aHUS in Patients with Complement Amplifying Conditions

aHUS Can Be Unmasked by Complement Amplifying Conditions1 Complement amplifying conditions present a situation where aHUS can be unmasked in patients experiencing TMA who may otherwise go undiagnosed1 Patients with aHUS are particularly susceptible to TMA when experiencing a complement amplifying condition2-5 As a result of this amplification, the complement cascade proceeds in an unrestricted manner5,6 References: 1. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859. 2. Noris M et al. Nat Rev Nephrol. 2012;8:622–633. 3. Liszewski MK et al. Hematol Am Soc Hematol Educ Program. 2011;2011:9–14. 4. Fang CJ et al. Br J Haematol. 2008;143:336-348. 5. Campistol JM et al. Nefrologia. 2013;33:27–45. 6. Noris M. New England Journal of Medicine. 2009;361:1676–1687.

69% of Patients With aHUS Showed Their First Clinical Manifestation while experiencing One of the Following Complement Amplifying Conditions 1 Diarrhoea/ Gastroenteritis 24% No Complement-amplifying Condition 31% Upper respiratory tract Infections 18% Others 12% Malignant Hypertension 8% Pregnancy 7% N=191 Reference: Noris M, Caprioli J, et al. 2010, Clin J Am Soc Neprhol 5: 1844-1859. 22

Outcomes in Patients with aHUS Associated with Pregnancy aHUS Unmasked by Pregnancy-Associated Complement Amplification Can Result in Significant and Permanent Renal Damage1 Fakhouri, et al. conducted a retrospective analysis of 100 adult female patients with aHUS from a national registry1 21% (21/100) of these patients presented with TMA during pregnancy or post-partum1 Outcomes in Patients with aHUS Associated with Pregnancy 81% 62% Patients, % (17/21) (13/21) Reference: 1. Fakhouri F et al. J Am Soc Nephrol 2010;21:859–867.

aHUS Is a Known Cause of Pregnancy-Associated TMA, including HELLP and post-partum HELLP1 aHUS is commonly unmasked post-partum, while TMA due to severe ADAMTS13 deficiency occurs more often during pregnancy1 79% of pregnancy-associated aHUS presented in the post-partum period2 History of a normal first pregnancy does not exclude a diagnosis of aHUS1 57% (12/21) of patients first presented with aHUS unmasked during a second or subsequent pregnancy1 Reference: 1. Fakhouri F et al. J Am Soc Nephrol 2010;21:859–867.

aHUS Is a Known Cause of TMA in Patients with Malignant Hypertension1,2 Patients with severe or malignant hypertension and an underlying complement mutation linked to aHUS are at high risk of TMA1-4 In malignant hypertension, complement activity can be amplified as the result of endothelial damage caused by shear stress to the vascular wall and vasoconstriction5 Malignant or severe hypertension is a known complication of aHUS1,7,8 TMA in patients with malignant or severe hypertension is associated with marked end-organ damage6 References: Barbour T et al. Nephrol Dial Transplant. 2012;27:2673-2685. Caprioli J et al; for the International Registry of Recurrent and Familial HUS/TTP. Blood. 2006;108:1267-1279. Geerdink LM et al. Pediatr Nephrol. 2012;27:1283-1291. Nadar SK et al. J Human Hypertens. 2007;21:261-263 Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844-1859. Noris M et al. Nat Rev Nephrol. 2012;8:622-633. Shibagaki Y et al. Hypertens Res. 2005;28:89-95. Totina A et al. Clin Pediatr (Phila). 2011;52:183-186. References: 1. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859. 2. Totina A et al. Clin Pediatr (Phila). 2011;52:183–186. 3. Nadar SK et al. J Human Hypertens. 2007;21:261–263. 4. Noris M et al. Nat Rev Nephrol. 2012;8:622–633. 5. Shibagaki Y et al. Hypertens Res. 2005;28:89-95. 6. Caprioli J et al; for the International Registry of Recurrent and Familial HUS/TTP. Blood. 2006;108:1267-1279. 7. Geerdink LM et al. Pediatr Nephrol. 2012;27:1283-1291. 8. Barbour T et al. Nephrol Dial Transplant. 2012;27:2673-2685.

aHUS Is a Known Cause of TMA in Patients with Systemic Lupus Erythematosus (SLE)1-4 Inability to remove immune complexes in SLE leads to increased complement activity and inflammatory injury5-7 aHUS may be underdiagnosed in patients with SLE1,4 aHUS complement mutations in patients with SLE are associated with earlier onset of nephritis2 Consider aHUS as a diagnosis in all patients presenting with SLE and TMA1,3,7,8 References: 1. Zhao J. PLoS Genet. 2011;7. 2. Jonsen A. Arthritis Res Ther. 2011;13:R206. 3. Noris M. Clin J Am Soc Nephrol. 2010;5:1844–1859. 4. Skerka C. Mol Immunol. 2013;56:170–180. 5. Ornstein BW. Curr Opin Rheumatol. 2012;24:522–529. 6. Chiu YY. J Investig Allergol Clin Immunol. 1998;8:239–244. 7. Song D. Arthritis Res Ther. 2013;15:R12. 8. Samson M. Internal Medicine Journal. 2012;42:95–98.

Summary aHUS is a chronic and life-threatening disease that arises from genetic abnormalities that result in uncontrolled activation of the complement system1,2 aHUS can clinically present similarly to other systemic TMAs, but the underlying complement-based disease pathophysiology warrants different management approaches3-6 PE/PI does not address the underlying complement dysfunction that causes aHUS1,2 aHUS is diagnosed clinically and relies on recognition of clinical symptoms and signs of TMA, evaluation of ADAMTS13 activity, and results of Shiga toxin testing as appropriate7-9 References: 1. Noris M et al. Clin J Am Soc Nephrol. 2010;5:1844–1859. 2. Caprioli et al. Blood. 2006;108:1267–1272. 3.George JN. Blood. 2010;116:4060–4069. 4. Noris M et al. N Engl J Med. 2009;361:1676–1687. 5. Zipfel PF et al. Curr Opin Nephrol Hypertens. 2010;19:372–378. 6. Bianchi V et al. Blood. 2002;100:710-713. 7. Ariceta G et al. European Paediatric Study Group for HUS. Pediatr Nephrol. 2009;24:687–696. 8. Kavanagh D et al. Br Med Bull. 2006;77-78:5–22. 9.Laurence J. Clin Adv Hematol Oncol. 2012;10 (10 Suppl 17):1-12. © 2015 Alexion Pharmaceuticals Australasia Pty Limited. All rights reserved. Alexion Pharmaceuticals Australasia Pty Limited. ACN 132 343 036. Suites 401, Level 4, Building A, 20 Rodborough Road Frenchs Forest NSW 2086. September 2015 AU/UNB-aHUS/15/0005